SX-682 and Nivolumab for the Treatment of RAS-Mutated, MSS Unresectable or Metastatic Colorectal Cancer, the STOPTRAFFIC-1 Trial

Inclusion Criteria: 1. Written Informed Consent and HIPAA Authorization 1. Subjects must have the nature of the study explained to them. 2. Non-English speaking patients will be eligible for participation with involvement of the MD Anderson Language Assistance department in the informed consent process (per MD Anderson SOP 04\_Informed Consent Process). 3. Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, pharmacokinetic collections, and other requirements of the study. 4. Subjects must provide a signed and dated IRB approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines for both the study and exploratory biomarker analyses (e.g., CMS4 and others) on archival tissue. 5. Subjects must provide a signed and dated Health Insurance Portability and Accountability Act (HIPAA) authorization. 6. The ICF and HIPAA authorization must be obtained before conducting any procedures that do not form a part of the subject's normal care. 7. After signing the ICF and HIPAA Authorization, subjects will be evaluated for study eligibility during the Screening Period (no more than 28 days before study drug administration) according to the following further inclusion/exclusion criteria: 2. Target Population 1. Men and women, ages \> 18 years of age. Both men and women of all races and ethnic groups, regardless of preferred language, are eligible for this trial. 2. Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum that is metastatic or unresectable. 3. Tumor is determined to be RAS-mutated (KRAS or NRAS) and microsatellite stable/proficient in mismatch repair, as assessed by IHC and/or PCR/NGS in a CLIA environment. 4. Received at least two prior regimens of therapy for unresectable or metastatic CRC including fluoropyrimidine-, oxaliplatin-, and irinotecan-based regimens. Patients who relapse within 6 months of adjuvant chemotherapy composed of oxaliplatin and a fluoropyrimidine will have their adjuvant therapy count as one prior regimen. 5. For the expansion cohort, pre-treatment primary tumor tissue (i.e., archived paraffin-embedded) or from an unresectable metastatic site must be available for biomarker analyses. Biopsy should be excisional or core needle. Fine needle aspirates or other cytology samples are insufficient. 6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (Appendix 1). 7. Must have measurable disease with at least 1 unidimensional measurable lesion per RECIST v1.1 (see Appendix 2). 8. Prior radiotherapy must have been completed at least 2 weeks prior to study drug administration. 9. Screening laboratory values must meet the following criteria and should be obtained within 14 days prior to first dose: WBC \> 3000/µL Neutrophils \> 1500/ µL Platelets \> 100,000/µL Hemoglobin \> 9.0 g/dL (may have been transfused) Creatinine \< 1.5 mg/dL AST/ALT \< 2.5 X ULN for subject with no liver metastases \< 5 X ULN for subjects with liver metastases Bilirubin \< 1.5 mg/dL (unless diagnosed with Gilbert's syndrome, who can have total bilirubin \< 3.0 mg/dL) INR or PT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy aPTT or PTT \< 1.5 X ULN unless the subject is receiving anticoagulant therapy 10. Glomerular filtration rate (GFR) calculated by Cockcroft-Gault formula \>60 ml/min. 11. Life expectancy \> 12 weeks as judged by the treating physician. 12. Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (i.e., subject has not been treated with SX-682). If re-enrolled, the subject must be re-consented. Exclusion Criteria 1. Target Disease Exceptions a) Active brain metastases or leptomeningeal metastases. Subjects with brain metastases are eligible if these have been treated and there is no magnetic resonance imaging (MRI - except where contraindicated, in which CT scan is acceptable) evidence of progression for at least 8 weeks after treatment is complete and within 28 days prior to first dose of study drug administration. An MRI is not required to rule out brain metastases or leptomeningeal metastases. There must also be no requirement for high doses of systemic corticosteroids that could result in immunosuppression (\> 10 mg/day prednisone equivalents) for at least 2 weeks prior to study drug administration. b) Patients with bulky liver metastases (liver metastases \>3cm) are not eligible. 2. Medical History and Concurrent Diseases a) Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results. Specifically: a. Subjects with active, non-infectious pneumonitis. b. Subjects with interstitial lung disease or a history of pneumonitis that required oral or intravenous glucocorticoids to assist with management. c. Subjects with clinically significant heart disease that affects normal activities. Clinically significant cardiovascular/ cerebrovascular disease as follows: cerebral vascular accident / stroke / carotid artery disease / transient ischemic attack (\<6 months prior to enrollment), myocardial infarction (\<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class \>II) or serious cardiac arrhythmia. b) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. c) Subjects with active, known or suspected autoimmune disease (Appendix 3). Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. d) Subjects with a condition (including organ or bone marrow transplant) requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications. Inhaled or topical steroids, and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. e) Use of other investigational drugs (drugs not marketed for any indication) or medications at immunosuppressive doses within 28 days before study drug administration. f) Prior exposure to any immune checkpoint blockade agent or any other immunomodulatory agent used for antineoplastic therapy for mCRC. g) Anticancer treatment within 21 days before the start of trial treatment \[e.g., cytoreductive therapy, radiotherapy (with the exception of palliative radiotherapy delivered in a normal organ-sparing technique), immune therapy, or cytokine therapy\]. Note: Patients on maintenance anti-hormonal treatment to prevent recurrence and secondary cancers are eligible for participation. h) Major surgery as determined by the investigator within 28 days before the start of trial treatment (prior diagnostic biopsy is permitted). i) Subjects who have received a live-virus vaccine within 30 days before study drug administration. j) Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to randomization/treatment. k) Patients who are taking any drug that is known to prolong QTc interval within at least 2 weeks before the start of trial drug and during the conduct of the trial. l) Individuals lacking the ability, based on reasonable medical judgment, to understand and appreciate the nature and consequences of participation in this study will not be eligible for participation